Composition and method for oral delivery of androgen prodrugs

ABSTRACT

Provided oral testosterone undecanoate compositions can be administered to hypogonadal males with a meal without the fat content of the meal substantially effecting bioavailability.

PRIORITY DATA

This application is a continuation of U.S. patent application Ser. No.15/183,691, filed Jun. 15, 2016, which claims the benefit of U.S.Provisional Application No. 62/175,931 filed Jun. 15, 2015 and U.S.Provisional Application No. 62/253,292 filed Nov. 10, 2015, each ofwhich are incorporated by reference in their entireties.

FIELD OF THE INVENTION

Described herein are methods of treatment with pharmaceuticalcompositions and dosage forms. Accordingly, the present disclosuregenerally involves health sciences, the fields of chemistry,pharmaceutical sciences, and medicine.

BACKGROUND OF THE INVENTION

A particularly difficult problem in regards to orally administeredlipophilic drugs is pharmacokinetic variability seen based on foodeffects. Many pharmaceuticals have important dosing requirements basedon the effect of food on their pharmacokinetics. Some pharmaceuticalsneed to be taken without food. Some pharmaceuticals need to be takenwith food. Other pharmaceuticals need to be taken with specific types offood. Yet other pharmaceuticals can be taken regardless of food. Morecomplicated or specific food requirements for dosing can lead to lessthan desirable efficacy or safety of the pharmaceutical since; ingeneral, a target population has quite variable eating habits. Forinstance, certain people are vegetarians, certain people may not eatbreakfast, certain people may have a low-fat diet, certain people mayhave a high-fat diet, and certain people have highly variable diets withrespect to fat content. These variables are difficult to control in areal world setting. Studies with Andriol Testocaps®, a testosteroneundecanoate containing oral product, have shown that meal fat contenthas substantial effects on the bioavailability of serum testosterone.Schnabel et al., Clinical Endocrinology (2007) 66, 579-585. Similarly,another testosterone undecanoate oral formulation being developed byClarus Therapeutics exhibits non-bioequivalency as a function of mealfat content. See Yin et al. J Androl. 2012 November-December; 33(6):1282-1290).

Thus, the present inventors recognize a need for oral formulations withtestosterone undecanoate bioavailability that is not substantiallyaltered by meal fat content.

SUMMARY OF THE INVENTION

The present disclosure is related to formulations and methods of orallyadministering formulations containing a lipophilic drug such astestosterone undecanoate (“TU”) or other testosterone esters.

The present inventors have surprisingly discovered oral testosteroneundecanoate compositions that can be effectively administered tohypogonadal males with a meal without the fat content of the mealsubstantially effecting bioavailability. This result is unexpected andin direct contrast to the bioavailability performance reported for manyother testosterone undecanoate oral formulations, which conclude thatbioavailability is affected by meal fat content.

Upon receipt of the information in this disclosure, the ordinarilyskilled artisan will be able to recognize oral testosterone undecanoateformulations that are bioequivalent to the formulations disclosedherein, including formulations that are bioequivalent for C_(max),AUC_((0-t)), AUC_((0-∞)), C_(avg), or a combination thereof at low,standard, and high fat conditions as well as standard versus low fat,standard versus high fat and low versus high fat for serum testosterone,testosterone undecanoate, dihydrotestosterone, dihydrotestosteroneundecanoate, or a combination thereof. Pharmaceutically equivalentformulations are also provided.

In view of the results described herein, a pharmaceutical composition isprovided that is bioequivalent for serum testosterone, testosteroneundecanoate, dihydrotestosterone, dihydrotestosterone undecanoate or acombination thereof for C_(max), AUC_((0-t)), AUC_((0-∞)), C_(avg), or acombination thereof for a standard meal versus either a low fat or highfat meal; for low, standard, and high fat meals; for low versus highfat. The pharmaceutical compositions or dosage forms can also bepharmaceutically equivalent.

Described herein are pharmaceutical compositions that are bioequivalentfor serum testosterone levels to a formulation having 50 mg to 350 mgtestosterone undecanoate (e.g., in one aspect either 75 mg or 112.5 mgTU) at about 15 wt % loading, about 63 wt % Maisine 35-1, about 16 wt %Cremophor RH 40 and about 6 wt % PEG 8000. The bioequivalent compositiontypically has from 10 wt %-50 wt % testosterone undecanoate and 50 wt%-90 wt % pharmaceutically acceptable carrier. The bioequivalentcompositions are bioequivalent for serum testosterone undecanoate,dihydrotestosterone, dihydrotestosterone undecanoate, or a combinationthereof for C_(max), AUC_((0-t)), AUC_((0-∞)), C_(avg), or a combinationthereof at low, standard, and high fat conditions as well as standardversus low fat, standard versus high fat and low versus high fat. Anycarrier can be used so long as the compositions are bioequivalent to theformulation having 50 mg to 350 mg testosterone undecanoate (e.g., inone aspect either 75 mg or 112.5 mg TU) at about 15 wt % loading, about63 wt % Maisine 35-1, about 16 wt % Cremophor RH 40 and about 6 wt % PEG8000. In some aspects, the formulation is also pharmaceuticallyequivalent to that described herein.

Also provided herein are methods for replacement therapy in a male forconditions associated with a deficiency or absence of endogenoustestosterone. The methods involve orally administering a pharmaceuticalcomposition having TU and a pharmaceutically acceptable carrier with ameal. The meal can be any meal regardless of fat content, the meal canalso be a low fat meal, a standard fat meal, or a high fat meal. Themethods provide bioequivalent C_(max), AUC_((0-t)), AUC_((0-∞)),C_(avg), or a combination thereof, when administered with any of lowfat, standard fat, or high fat meals. Alternatively, the methods providebioequivalent C_(max), AUC_((0-t)), AUC_((0-∞)), C_(avg), or acombination thereof, when administered with a standard fat meal ascompared to low or high fat meals. In another alternative, the methodprovides bioequivalent C_(max), AUC_((0-t)), AUC_((0-∞)), C_(avg), or acombination thereof when administered with a low fat meal as compared toa high fat meal. When the composition is administered with a TU totaldaily dose range of about 275 mg (e.g., 300 mg) to about 625 mg (e.g.,600 mg), the composition provides a serum testosterone C_(avg) at steadystate in the range of 300 ng/dL to about 1100 ng/dL to a subject in needof treatment. The methods can include a dose titration as describedherein.

Thus, the results described herein support a drug label indicating (ormethod involving) that the oral testosterone replacement therapy(testosterone undecanoate containing oral dosage form) is taken (1)“WITH A MEAL” or (2) “WITH MEAL, BUT NOT ON EMPTY STOMACH” or (3) “WITHFAT CONTAINING FOOD” not specifying fat content. In an alternative, thedrug label may indicate (or method may involve) the oral testosteronereplacement therapy (testosterone undecanoate containing oral dosageform) is taken “WITH MEAL, BUT NOT LOW FAT”. In an alternative, the druglabel may indicate (or method may involve) the oral testosteronereplacement therapy (testosterone undecanoate containing oral dosageform) is taken “WITH MEAL, BUT NOT HIGH FAT”. In an alternative, thedrug label may indicate (or method may involve) the oral testosteronereplacement therapy (testosterone undecanoate containing oral dosageform) is taken “WITH STANDARD OR NORMAL MEAL”.

DETAILED DESCRIPTION

Before the present testosterone undecanoate compositions, oral dosageforms, such as capsules, and related methods of use are disclosed anddescribed in more detail and variations, it is to be understood thatthis invention is not limited to the particular process steps andmaterials disclosed herein, but is extended to equivalents thereof, aswould be recognized by those ordinarily skilled in the relevant arts. Itshould also be understood that terminology employed herein is used forthe purpose of describing particular embodiments only and is notintended to be limiting.

In specific embodiments, provided herein are the following:

(1) A method for replacement therapy in a male for conditions associatedwith a deficiency or absence of endogenous testosterone, said methodcomprising: orally administering to a male having a condition associatedwith a deficiency or absence of endogenous testosterone, with a meal, apharmaceutical composition comprising from about 50 mg to about 300 mgof testosterone undecanoate and a pharmaceutically acceptable carriersaid pharmaceutical acceptable carrier being selected to providebioequivalent amounts of serum testosterone, testosterone undecanoate,dihydrotestosterone or dihydrotestosterone undecanoate levels to saidmale for (i) meals containing standard fat as compared to low fat andhigh fat, (ii) for meals containing low fat as compared to high fat, orboth (i) and (ii).(2) The method as in 1, said pharmaceutical composition having about 75mg, about 112.5 mg, about 150 mg, about 225 mg, or about 300 mg oftestosterone undecanoate.(3) The method as in 1, said pharmaceutical acceptable carrier selectedto provide bioequivalent amounts of serum testosterone levels to saidmale for meals containing low fat, standard fat and high fat.(4) The method as in 1, said method providing a serum testosteroneC_(avg) in the range of 300 ng/dL to 1100 ng/dL.(5) The method as in 1, wherein said administering is twice-a-day.(6) The method as in 1, said method comprising administering from 285 mgto about 625 mg of testosterone undecanoate per day.(7) The method as in 1, said composition comprising a lipophilicadditive.(8) The method as in 1, said composition comprising a hydrophilicadditive.(9) The method as in 1, said pharmaceutical composition (i) beingpharmaceutically equivalent to an oral pharmaceutical composition havingabout 75 mg or about 112.5 mg of testosterone undecanoate at about 15 wt% loading, about 63 wt % Maisine 35-1 (glyceryl monolinoleate), about 16wt % Cremophor RH 40 (Polyoxyl 40 hydrogenated castor oil) and about 6wt % PEG 8000 (polyethylene glycol having an average molecular weight of8,000 grams/mole) or (ii) has about 75 mg or about 112.5 mg oftestosterone undecanoate at about 15 wt % loading, about 63 wt % Maisine35-1, about 16 wt % Cremophor RH 40 and about 6 wt % PEG 8000.(10) The method as in 1, said method comprising administering thepharmaceutical composition as 2, 3, 4, 5, 6, 7, or 8 unit dosage formsper day.(11) A method for replacement therapy in a male for conditionsassociated with a deficiency or absence of endogenous testosterone, saidmethod comprising: orally administering to a male having a conditionassociated with a deficiency or absence of endogenous testosterone, witha meal having about 10 wt % to 50 wt % fat, a pharmaceutical compositioncomprising from about 50 mg to about 300 mg of testosterone undecanoateand a pharmaceutically acceptable carrier said pharmaceutical acceptablecarrier is selected to provide bioequivalent amounts of serumtestosterone, testosterone undecanoate, dihydrotestosterone ordihydrotestosterone undecanoate levels to said male for meals containing(i) standard fat as compared to low fat and high fat, (ii) low fat tohigh fat or (iii) a combination thereof.(12) The method as in 11, said pharmaceutical composition (i) beingpharmaceutically equivalent to an oral pharmaceutical composition havingabout 75 mg or about 112.5 mg of testosterone undecanoate at about 15 wt% loading, about 63 wt % Maisine 35-1, about 16 wt % Cremophor RH 40 andabout 6 wt % PEG 8000 or (ii) has about 75 mg or about 112.5 mg oftestosterone undecanoate at about 15 wt % loading, about 63 wt % Maisine35-1, about 16 wt % Cremophor RH 40 and about 6 wt % PEG 8000.(13) The method as in 11, said method providing a serum testosteroneCavg in the range of 300 ng/dL to 1100 ng/dL.(14) The method as in 11, said method comprising administering from 285mg to about 625 mg of testosterone undecanoate per day.(15) The method as in 11, wherein said administering is twice-a-day.(16) A pharmaceutical composition for oral administration comprisingtestosterone undecanoate and a pharmaceutical acceptable carrier saidpharmaceutical composition providing bioequivalent amounts of serumtestosterone undecanoate, testosterone, dihydrotestosterone,dihydrotestosterone undecanoate or a combination thereof to a male forconditions associated with a deficiency or absence of endogenoustestosterone when administered with a meal (i) containing medium fat ascompared to high fat or low fat or (ii) containing low, standard, orhigh fat.(17) The pharmaceutical composition as in 16, said pharmaceuticalcomposition being pharmaceutical equivalent to an oral pharmaceuticalcomposition having about 75 mg or about 112.5 mg of testosteroneundecanoate at 15 wt % loading, 63 wt % Maisine 35-1, 16 wt % CremophorRH 40, and 6 wt % PEG 8000.(18) The pharmaceutical composition as in 16 comprising a monoglyceride,a diglyceride or a combination thereof in amount of greater than about10 wt % and has less than about 50 wt % triglyceride.(19) A pharmaceutical composition for oral administration that ishypogonadal male serum testosterone bioequivalent to a formulationcomprising 15 wt % testosterone undecanoate, about 63 wt % Maisine 35-1,about 16 wt % Cremophor RH 40, and about 6 wt % polyethylene glycol 8000under medium fat as compared to low fat and high fat with the provisothat the formulation does not comprises about 15 wt % testosteroneundecanoate, about 63 wt % Maisine 35-1, about 16 wt % Cremophor RH 40,and about 6 wt % polyethylene glycol 8000.(20) The pharmaceutical composition as in 19, said pharmaceuticalcomposition being pharmaceutically equivalent to an oral pharmaceuticalcomposition having about 75 mg or about 112.5 mg of testosteroneundecanoate at 15 wt % loading, 63 wt % Maisine 35-1, 16 wt % CremophorRH 40, and 6 wt % PEG 8000.(21) The pharmaceutical composition as in 19, comprising amonoglyceride, a diglyceride or a combination thereof in amount ofgreater than 10 wt % and has less than 50 wt % triglyceride.(22) A pharmaceutical composition for oral administration forreplacement therapy in a male for conditions associated with adeficiency or absence of endogenous testosterone comprising testosteroneundecanoate and a pharmaceutical acceptable carrier said pharmaceuticalcomposition indicated to be taken (i) “WITH A MEAL”, (ii) “WITH MEAL,BUT NOT ON EMPTY STOMACH”, (iii) “WITH FAT CONTAINING FOOD” notspecifying fat content, (iv) “WITH MEAL, BUT NOT LOW FAT”, (v) “WITHMEAL, BUT NOT HIGH FAT”, or (vi) “WITH STANDARD OR NORMAL MEAL”.(23) The pharmaceutical composition as in 22, said pharmaceuticalcomposition indicated to be taken “WITH A MEAL”.(24) The pharmaceutical composition as in 22, said pharmaceuticalcomposition indicated to be taken “WITH MEAL, BUT NOT ON EMPTY STOMACH”.(25) The pharmaceutical composition as in 22, said pharmaceuticalcomposition indicated to be taken “WITH FAT CONTAINING FOOD” notspecifying fat content.(26) The pharmaceutical composition as in 22, said pharmaceuticalcomposition indicated to be taken “WITH MEAL, BUT NOT LOW FAT”.(27) The pharmaceutical composition as in 22, said pharmaceuticalcomposition indicated to be taken “WITH MEAL, BUT NOT HIGH FAT”.(28) The pharmaceutical composition as in 22, said pharmaceuticalcomposition indicated to be taken “WITH STANDARD OR NORMAL MEAL”(29) The method of any one of 1-15 further comprising a dose titrationof testosterone undecanoate.(30) The method of any one of 1-15 or 29 with a pharmaceuticalcomposition as in any one of 16-29 to the extent the methods andcompositions are not inconsistent with one another.(31) The pharmaceutical composition of any one of claims 16-28 disposedor contained in a capsule.(32) The pharmaceutical composition as in 22, indicated to be taken witha meal having at least 10 grams or about 10 grams of fat.(33) The pharmaceutical composition as in 22, indicated to be taken witha meal having at least 15 grams or about 15 grams of fat.(34) An oral dosage form in a container that includes a container havinga label and an oral dosage form contained within the container. The oraldosage form can include testosterone undecanoate and a pharmaceuticallyacceptable carrier. The label on the container can indicate that theoral dosage form is to be taken (1) “WITH A MEAL”, (2) “WITH MEAL, BUTNOT ON EMPTY STOMACH”, (3) “WITH FAT CONTAINING FOOD” not specifying fatcontent, (4) “WITH MEAL, BUT NOT LOW FAT”, (5) “WITH MEAL, BUT NOT HIGHFAT”, or (6) “WITH STANDARD OR NORMAL MEAL”.(35) The oral dosage form as in 34, wherein the container is selectedfrom a bottle, a pouch, or a blister package.

It should be noted that as used in this written description, thesingular forms “a,” “an,” and, “the” include express support for pluralreferents unless the context clearly dictates otherwise. Thus, forexample, reference to “an excipient” includes support for one or more ofsuch excipients, and reference to “the carrier” includes support for oneor more of such carriers.

Definitions

As used herein, “pharmaceutically equivalent”, refers to a compositionor unit dosage form drug product if they meet three criteria: theycontain the same active ingredient(s); they are of the same dosage formand route of administration; they are identical in strength orconcentration. Typically, pharmaceutical equivalent drug products maydiffer in characteristics such as shape, release mechanism, labeling (tosome extent), scoring and excipients (including colors, flavors,preservatives) although this list in not-limiting.

As used herein, “bioequivalent”, refers to the absence of a significantdifference in the rate and extent to which the active ingredient oractive moiety in pharmaceutical equivalents or pharmaceuticalalternatives becomes available at the site of drug action whenadministered at the same dose under similar conditions in anappropriately designed study. Two products are bioequivalent if the 90%CI (Confidence Interval) of the relative mean C_(max), AUC_((0-t)),AUC_((0-∞)) of the test (e.g., generic formulation) to reference (e.g.,innovator brand formulation) should be within 70% to 143% and preferably80.00% to 125.00% under particular conditions e.g., fed, fasted,particular fat content in meals (e.g., low, standard, or high). Unlessotherwise specified, bioequivalence can be for serum testosteroneundecanoate, serum testosterone, serum dihydrotestosterone or serumdihydrotestosterone undecanoate. Typically, bioequivalence is determinedwith a group of subjects.

As used herein, the term “treatment,” when used in conjunction with theadministration of pharmaceutical compositions and oral dosage capsulescontaining testosterone undecanoate, refers to the administration of theoral dosage capsules and pharmaceutically acceptable composition tosubjects who are either asymptomatic or symptomatic. In other words,“treatment” can both be to reduce or eliminate symptoms associated witha condition present in a subject, or it can be prophylactic treatment,i.e., to prevent the occurrence of the symptoms in a subject. Suchprophylactic treatment can also be referred to as prevention of thecondition.

As used herein, the terms “formulation” and “composition” are usedinterchangeably and refer to a mixture of two or more compounds,elements, or molecules. In some aspects the terms “formulation” and“composition” may be used to refer to a mixture of one or more activeagents with a carrier or other excipients. Furthermore, the term “dosageform” can include one or more formulation(s) or composition(s) providedin a format for administration to a subject. When any of the above termsis modified by the term “oral” such terms refer to compositions,formulations, or dosage forms formulated and intended for oraladministration to subjects.

As used herein, the term “fatty acid” refers to unionized carboxylicacids with a long aliphatic tail (chain), either saturated orunsaturated, conjugated or non-conjugated. Typically, the fatty acid isa C₈ to C₂₂ fatty acid.

Unless otherwise specified, the term C₈ to C₂₂ fatty acid glyceridesrefers to a mixture of mono-, di-, and/or tri-glycerol esters of mediumto long chain (C₈ to C₂₂) fatty acids.

As used herein, the term “solidifying agent” or “solidifying additive”are used interchangeably and refer to a pharmaceutically acceptableadditive that is in a solid physical state at 20° C. Similarly, a “solidlipophilic additive” refers to a lipophilic compound or component thatis in a solid physical state at 20° C. and/or renders the composition ordosage form non-liquid, such as solid or semi-solid.

As used herein, the term “lipophilic,” refers to compounds that are notfreely soluble in water; and the term “lipophilic surfactant” refers tosurfactants that have HLB values of about 10 or less. Conversely, theterm “hydrophilic” refers to compounds that are soluble in water; andterm “hydrophilic surfactant” refers to surfactants that have HLB valuesof more than about 10.

As used herein, the term “ionizable fatty acid” refers to a fatty acidcompound that changes its HLB as a function of pH. For example, oleicacid is predominantly lipophilic at lower pH values (such as those foundin the stomach) but becomes a predominantly hydrophilic at higher pHvalues (such as those found in the intestine).

As used herein, “subject” refers to a mammal that may benefit from theadministration of a drug composition or method of this invention.Examples of subjects include humans. In one aspect, the subject can be ahuman male. In another embodiment, the subject can be a hypogonadalmale. In one aspect, the subject is a male in need of replacementtherapy for conditions associated with a deficiency or absence ofendogenous testosterone. As used herein, the testosterone deficiency orhypogonadism in a male human subject (hypogonadal male) refers to acondition wherein the average baseline plasma testosterone concentration(T-C_(avg-B)) is about 300 ng/dL or less. However, in some instances,testosterone deficiency or hypogonadism in a male human subject refersto a condition wherein the average baseline plasma testosteroneconcentration is about 400 ng/dL or less.

As used herein, “group” or “group of subjects” refers to a collection ofat least 12 human male subjects who receive and respond to exogenousoral administration of the compositions disclosed herein, namelytestosterone undecanoate-containing compositions. In one aspect, thegroup can include at least 100 or at least 300 male subjects. In anotheraspect, the group can include at least 1000 male subjects. In anotherembodiment, the subjects can be hypogonadal subjects.

The term “oral administration” represents any method of administrationin which an active agent can be administered by swallowing, chewing, orsucking of the dosage form. The composition of the current inventionscan be admixed with food or drink prior to being orally consumed.

As used herein, a “dosing regimen” or “regimen” such as an “initialdosing regimen” or a “maintenance dosing regimen” refers to how, when,how much, and for how long a dose of the compositions of the presentinvention can be administered to a subject. For example, an initialdosing regimen for a hypogonadal male subject may provide for a totaldaily dose of 450 mg administered in two divided doses at about 12 hoursapart (e.g., once with breakfast and once with dinner) with meals (e.g.,having about 10 g to 55 g of fat content, or any other appropriate meal)repeated daily for at least one week, two weeks or 30 days.

As used herein, “daily dose” refers to the amount of active agent (e.g.,testosterone undecanoate) administered to a subject over a 24-hourperiod of time (e.g., per day). The daily dose can be administered asone or two or more administrations during the 24 hour period(twice-a-day). In one embodiment, the daily dose provides for twoadministrations in a 24 hour period. With this in mind, an “initialdose” or initial daily dose” refers to a dose administered during theinitial regimen or period of a dosing regimen. An initial dose includesboth the very first dose during the initial regimen as well as thesubsequent doses during the same initial regimen. Similarly, a“maintenance dose” or “maintenance daily dose” refers to a doseadministered during a maintenance regimen of a dosing regimen. It isworth noting that the maintenance dose follows a dose titration based onthe serum testosterone determination on a titration node day (after asingle dose of the initial daily dose at steady state), however themaintenance dose does not need to be of a different quantity as theinitial dose or the previous maintenance dose (in the case of multipletitrations).

As used herein, the term “solidifying agent” or “solidifying additive”are used interchangeably and refer to a pharmaceutically acceptableadditive that is in a solid physical state at 20° C. Similarly, a “solidlipophilic additive” refers to a lipophilic compound or component thatis in a solid physical state at 20° C. and/or renders the composition ordosage form non-liquid, such as solid or semi-solid.

As used herein, “non-liquid” when used to refer to the state of acomposition disclosed herein refers to the physical state of thecomposition as being a semi-solid or solid. As used herein, “solid” and“semi-solid” refers to the physical state of a composition that supportsits own weight at standard temperature and pressure, and has adequateviscosity or structure to not freely flow. Semi-solid materials mayconform to the shape of a container under applied pressure.

As used herein, “titration” or “dose titration” or “dose adjustment” areused interchangeably and refer to an increase or decrease of the totaldaily dose of testosterone undecanoate administered to a subject,typically based on the response of the subject to the exogenousadministered testosterone undecanoate. The dose can be increased ordecreased based on the measurement of serum testosterone concentrationafter a steady state has been achieved.

As used herein, “steady state” refers to the achievement of a stableresponse in serum total testosterone levels to exogenously administeredtestosterone undecanoate, typically achieved after at least 15 daysfollowing the start of a dosing regimen.

As used herein, “initial daily dose” (IDD) or “Daily dose of the initialregimen” is a dose of testosterone undecanoate administered daily to asubject in need of testosterone therapy. The initial daily dose may beadministered in one or two or more intervals over a 24-hour period,e.g., twice-a-day. Similarly, “maintenance daily dose” or “daily dose ofthe maintenance regimen” is a dose of testosterone undecanoateadministered daily to a subject in need of testosterone therapy asdetermined based on measurement of the titration node day titrationmetric and is the daily dose going forward within a few days ofmeasurement unless a dose change is needed based on a another titrationnode day measurement. During a maintenance regimen there may be one ortwo or more daily doses administered which at some point during theregime would be considered to be the maintenance daily dose.

As used herein, “titration node” or “titration node day” are usedinterchangeably and refer to a day on which a serum sample is drawn froma subject for measurement of the serum testosterone concentrations inorder to determine whether a testosterone undecanoate dose titration isnecessary and what the titration type might need to be. The measuredserum testosterone levels may also be used to determine dose a titrationmetric to be utilized in deciding dose titration needs for an individualsubject. As dosing regimens can include one or more titration node daythe term may refer to a first titration node during a dosing regimen(e.g., between the initial dosing regimen and the maintenance dosingregimen) or it can refer to a subsequent titration node day between amaintenance dosing regimen and a subsequent maintenance dosing regimen.

As used herein, the terms “release” and “release rate” are usedinterchangeably to refer to the discharge or liberation of a substance,including without limitation a drug, from the dosage form into asurrounding environment such as an aqueous medium either in vitro or invivo.

As used herein, an “effective amount” or a “therapeutically effectiveamount” of a drug refers to a non-toxic, but sufficient amount of thedrug, to achieve therapeutic results in treating a condition for whichthe drug is known to be effective. It is understood that variousbiological factors may affect the ability of a substance to perform itsintended task. Therefore, an “effective amount” or a “therapeuticallyeffective amount” may be dependent in some instances on such biologicalfactors. Further, while the achievement of therapeutic effects may bemeasured by a physician or other qualified medical personnel usingevaluations known in the art, it is recognized that individual variationand response to treatments may make the achievement of therapeuticeffects a somewhat subjective decision. The determination of aneffective amount is well within the ordinary skill in the art ofpharmaceutical sciences and medicine. See, for example, Meiner andTonascia, “Clinical Trials: Design, Conduct, and Analysis,” Monographsin Epidemiology and Biostatistics, Vol. 8 (1986), incorporated herein byreference.

The terms “plasma testosterone concentration,” “testosteroneconcentration in the blood,” and “serum testosterone concentration” areused interchangeably and refer to the “total” testosterone concentrationwhich is the sum of the bioavailable testosterone including free andprotein-bound testosterone concentrations. As with any bio-analyticalmeasure, for increased consistency the method employed to measureinitial serum testosterone levels should be consistent with the methodused to monitor and re-measure serum testosterone levels during clinicaltesting and testosterone therapy for a subject. Likewise, serum orplasma (used interchangeably) testosterone undecanoate and themetabolites dihydrotestosterone and dihydrotestosterone undecanoate, canbe determined by the ordinary skilled artisan.

As used herein, of the average serum testosterone concentration can bedetermined using methods and practices known in the art. For example,the average baseline plasma testosterone concentration of a human maleis the arithmetic mean of the total plasma testosterone concentrationsdetermined on at least two consecutive time points that are reasonablyspaced from each other, for example from about 1 hour to about 168 hoursapart. In a particular case, the plasma testosterone concentration canbe determined on at least two consecutive times that are about 12 hoursto about 48 hours apart. In another particular method, the plasmatestosterone concentration of the human male can be determined at a timebetween about 5 am and about 11 am. Further, the plasma testosteroneconcentration can be the determined by standard analytical proceduresand methods available in the art, such as for example, automated ormanual immunoassay methods, liquid chromatography or liquidchromatography-tandem mass spectrometry (LC-MSMS) etc.

As used herein, the term AUC_(0-t) is the area under the curve of aplasma-versus-time graph determined for the analyte from the time 0 totime “t”.

As used herein, the term “C_(avg),” “C_(ave),” or “C-average” are usedinterchangeably, and is determined as the AUC_(0-t) or the mean AUCdivided by the time period (t). For example, C_(avg-8h) is the averageplasma concentration over a period of 8 hours post-dosing determined bydividing the AUC₀₋₈ value by 8. Similarly, C_(avg-12h) is the averageplasma concentration over a period of 12 hours post-dosing determined bydividing the AUC₀₋₁₂ value by 12; C_(avg-24h) is the average plasmaconcentration over a period of 24 hours post-dosing determined bydividing the AUC_(0-24h) value by 24, and so on. Unless otherwisestated, all C_(ave) values are considered to be C_(ave-24h).

As used herein “C_(max)” refers to the maximum measured serumconcentration of the administered drug or a metabolite after single doseadministration.

As used herein, “free of” or “substantially free of” of a particularcompound or compositions refers to the absence of any separately addedportion of the referenced compound or composition. Free of orsubstantially free of can include the presence of 1 wt % or less (basedon total composition weight) of the referenced compound which may bepresent as a component or impurity of one or more of the ingredients.

As used herein, the term “TU” refers to testosterone undecanoate.

As used herein, “with a meal” generally means within an hour of a meal(e.g., plus/minus an hour or preferably within 30 minutes). Morepreferably, “with a meal” means within 30 minutes of a meal e.g., within30 minutes after the subject has eaten a meal. Even more preferably,“with a meal” refers to about 30 minutes after the subject has eaten ameal.

As used herein, the terms “meal” and “food” can be used interchangeably.

As used herein, “low fat” or “low fat meal” generally refers a mealhaving less than about 30 grams of fat. For example, in some cases, “lowfat” or “low fat meal” refers to a meal having from about 10 grams toabout 30 grams of fat, or about 10 grams to about 25 grams of fat, orabout 15 grams to about 25 grams of fat, or about 15 grams of fat.

As used herein, “medium fat,” “medium fat meal,” “standard fat,”“standard meal,” or “standard fat meal” generally refers to a mealhaving from about 20 grams of fat to about 50 grams of fat. For example,in some cases, “medium fat,” “medium fat meal,” “standard fat,”“standard meal,” or “standard fat meal” refer to a meal having fromabout 20 grams to about 45 grams of fat, about 20 grams to about 40grams of fat, about 25 grams to about 35 grams of fat, or about 30 gramsof fat.

As used herein, “high fat” or “high fat meal” generally refers to a mealhaving 40 or more grams of fat. For example, in some cases, “high fat”or “high fat meal” can refer to a meal having from about 40 to about 100grams of fat, about 45 grams to about 100 grams of fat, about 45 gramsto about 90 grams of fat, about 45 to about 75 grams of fat, about 45grams to about 60 grams of fat, or about 50 grams. Further, in someother examples, “high fat meal” can be a meal having greater than 45grams of fat or a meal having greater than 50 grams of fat.

As used herein, the term “about” is used to provide flexibility to anumerical range endpoint by providing that a given value may be “alittle above” or “a little below” the endpoint. As used herein, aplurality of items, structural elements, compositional elements, and/ormaterials may be presented in a common list for convenience. However,these lists should be construed as though each member of the list isindividually identified as a separate and unique member. Thus, noindividual member of such list should be construed as a de factoequivalent of any other member of the same list solely based on theirpresentation in a common group without indications to the contrary.

As used herein, a plurality of items, structural elements, compositionalelements, and/or materials may be presented in a common list forconvenience. However, these lists should be construed as though eachmember of the list is individually identified as a separate and uniquemember. Thus, no individual member of such list should be construed as ade facto equivalent of any other member of the same list solely based ontheir presentation in a common group without indications to thecontrary.

Concentrations, amounts, levels and other numerical data may beexpressed or presented herein in a range format. It is to be understoodthat such a range format is used merely for convenience and brevity andthus should be interpreted flexibly to include not only the numericalvalues explicitly recited as the limits of the range, but also toinclude all the individual numerical values or sub-ranges or decimalunits encompassed within that range as if each numerical value andsub-range is explicitly recited. As an illustration, a numerical rangeof “about 1 to about 5” should be interpreted to include not only theexplicitly recited values of about 1 to about 5, but also includeindividual values and sub-ranges within the indicated range. Thus,included in this numerical range are individual values such as 2, 3, and4 and sub-ranges such as from 1-3, from 2-4, and from 3-5, etc., as wellas 1, 2, 3, 4, and 5, individually. This same principle applies toranges reciting only one numerical value as a minimum or a maximum.Furthermore, such an interpretation should apply regardless of thebreadth of the range or the characteristics being described.

Described herein are formulations and methods of using thoseformulations for testosterone replacement therapy. The formulationsdescribed herein are for oral administration for replacement therapy ina male for conditions associated with a deficiency or absence ofendogenous testosterone (e.g., a hypogonadal male or a male experiencinga symptom of testosterone deficiency). In some aspects, the therapy canbe used in females.

It is noted that testosterone deficiency can typically be associatedwith a variety of conditions, each of which can cause or contribute tothe deficiency or absence of testosterone in a subject. The compositionsand oral dosage capsules of the present invention can be used to treatany condition associated with testosterone deficiency, includingcomplete absence, of endogenous testosterone. Examples of conditionsassociated with testosterone deficiency that can be treated using theoral dosage capsules and/or compositions of the present inventioninclude, but are not limited to congenital or acquired primaryhypogonadism, hypogonadotropic hypogonadism, cryptorchidism, bilateraltorsion, orchitis, vanishing testis syndrome, orchidectomy,Klinefelter's syndrome, post castration, eunuchoidism, hypopituitarism,endocrine impotence, infertility due to spermatogenic disorders,impotence, male sexual dysfunction (MSD) including conditions such aspremature ejaculation, erectile dysfunction, decreased libido, and thelike, micropenis and constitutional delay, penile enlargement, appetitestimulation, testosterone deficiency associated with chemotherapy,testosterone deficiency associated with toxic damage from alcohol, heavymetal, or other substances, osteoporosis associated with androgendeficiency, late-onset hypogonadism (e.g., age-related), or combinationsthereof.

Additionally, the compositions and oral dosage forms disclosed hereininclude can also be used to treat idiopathic gonadotropin, LHRHdeficiency, or pituitary hypothalamic injury from tumors, trauma, orradiation. Typically, these subjects have low serum testosterone levelsbut have gonadotropins in the normal or low range. In one embodiment,the compositions or oral dosage forms can be used to stimulate pubertyin carefully selected males with clearly delayed puberty not secondaryto pathological disorder. In another embodiment, the compositions andoral dosage forms can be used in female-to-male transsexuals in order tomaintain or restore male physical and sexual characteristics includingbody muscle mass, muscle tone, bone density, body mass index (BMI),enhanced energy, motivation and endurance, restoring psychosexualactivity, etc. In some embodiments, the testosterone undecanoatecompositions and oral dosage capsules can be useful in providinghormonal male contraception.

Additionally, testosterone therapy can also be used to improve thequality of life of subjects suffering from conditions such as decreasedlibido, diminishing memory, anemia due to marrow failure, renal failure,chronic respiratory or cardiac failure, steroid-dependent autoimmunedisease, muscle wasting associated with various diseases such as AIDS,preventing attacks of hereditary angioedema or urticaria; andropause,and palliating terminal breast cancer. In some situations, certainbiomarkers such as for example, increased SHBG levels, can be used todiagnose a subject who may be in need of testosterone therapy. Thesebiomarkers can be associated with conditions/disease states such asanorexia nervosa, hyperthyroidism, hypogonadism, androgeninsensitivity/deficiency, alcoholic hepatic cirrhosis, primary biliarycirrhosis, and the like.”

In one specific embodiment, formulations and oral dosage forms asdescribed herein can be used to treat primary hypogonadism (congenitalor acquired) or hypogonadotropic hypogonadism (congenital or acquired).

The formulations can be any formulation having a testosterone estere.g., testosterone undecanoate and one or more carriers. The carriersare selected such that the formulation, when administered orally forreplacement therapy in a male for conditions associated with adeficiency or absence of endogenous testosterone, produces bioequivalentserum testosterone levels when administered with low, standard, or highfat meals. Bioequivalence can be determined by an ordinary skilledartisan in view of Examples described herein. The carriers and amountsthereof are selected such that the formulation provides bioequivalentlevels of serum testosterone when administered under high fat mealsversus low fat meals, standard meals versus low fat meals, standardmeals versus high fat meals, or low, standard, or high fat meals.

In one embodiment, the composition or oral dosage form can beadministered with a meal, such as a meal that provides about 200calories to about 1000 calories of food energy. In another embodiment,the composition or oral dosage form can be administered with a meal thatprovides about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%,60%, 70%, 80%, 90% or 100% of the calories from the fat (or within arange derived from any combination of these values). In yet anotherembodiment, the composition or oral dosage form can be administered witha meal that provides about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%,or 50% of the calories from the fat (or within a range derived from anycombination of these values). In yet another embodiment, the compositionof oral dosage form can be administered with a meal that provides about10% to about 50% of the calories from the fat. In one aspect, whereabout 10% to about 50% of the calories are from the fat, the meal caninclude at least 10 grams or at least 15 grams of fat. In anotherembodiment, the composition or oral dosage form can be administered witha high-fat, high calorie meal. In another embodiment, the composition ororal dosage form can be administered with a standard meal that providesabout 500 calories to about 1000 calories of energy. The compositionalmake-up of the meals that are administered can vary depending on thetastes and dietary needs of a subject. However, in some situations itmay be beneficial to administer the compositions and oral dosage formswith meals that provide no fat to about 100 g of fat. In one embodiment,the meal can provide about 10 g to about 50 g of fat. In yet a furtherembodiment, the meal can provide 15 g to about 35 g of fat. In yet afurther embodiment, the meal can provide about 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26,27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44,45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60 gramsof fat (or within a range derived from any combination of these values).

It is noted that any type of food or meal can be used in the methods andwith the compositions described herein depending on the particularembodiment or aspect of the invention. Typically, the amount of fat orcalories per serving is available on the food label or otherwiseprovided, such as by a restaurant. Fat content or calories in food andmeals can also be determined or estimated by an individual using themethods and compositions disclosed herein by consulting typical books onnutrition or nutritional databases such as those provided by the USDA(United States Department of Agriculture) which are available online.

Exemplary, breakfasts and foods with ≥15 g fat are given below, asprovided by the USDA Nutrient Database (each of which can be modified toachieve a desired fat content, calorie content, or combination thereof,and are not intended to be limiting examples). The fat and caloriecontent of food or dinner meals can be similarly determined byconsulting label information, online information and databases,nutrition books, information provided by restaurants, and the like.

1 cup toasted wheat germ cereal (12 g)+1 cup lowfat (2%) milk (5 g): 17g fat

1 slice whole wheat toast (1 g)+2 Tablespoons peanut butter (16 g): 17 gfat

1 small bagel (1.5 g)+1.5 oz cream cheese (15 g): 16.5 g fat

½ cup homemade granola cereal (15 g): 15 g fat

2 boiled eggs (10 g)+1 oz turkey bacon (5 g): 15 g fat

2 boiled eggs (10 g)+1 slice whole wheat toast (1 g)+1 teaspoon butter(4 g): 15 g fat

1 medium butter croissant (12 g)+coffee with 1 Tablespoon cream (3 g):15 g fat

¼ cup almonds, whole: 18 g fat

¼ cup sunflower seeds: 18 g fat

2 oz cheddar cheese: 18 g fat

Other non-limiting examples of foods or meals that a subject can havewith the compositions and methods disclosed herein can include, forexample:

Mega Melt with Reg eggs, 6″ sandwich, hash browns, 12 fl oz orangejuice: 36 g fat (1014 kcal)

6″ Subway Melt Omelet Sandwich with regular egg, hash browns, 12 fl ozorange juice: 37 g fat (1074 kcal)

6″ sausage, eggs & cheese omelet sandwich, hash browns, 12 fl oz orangejuice: 29 g fat (854 kcal)

Bacon, egg & cheese on 3″ flatbread, hash brown, 12 fl oz orange juice:28 g fat (814 kcal)

McDonalds hotcakes with sausage, syrup, hash browns: 33 g fat (850kcal);

Fruit & maple oatmeal, hash browns, egg McMuffin, nonfat Latte: 34 g fat(980 kcal)

Panera cinnamon roll and strawberry granola parfait: 35 g fat (940 kcal)

Starbuck's bacon and gouda Artisan breakfast sandwich, steel cut oatmealwith blueberry topping, and greek yogurt with berries parfait: 31 g fat(920 kcal)

As will be recognized by one skilled in the art, there are numerousother food or meal options that can be used to arrive at a low, medium,or high fat meal.

Whether or not the compositions or oral dosage forms described hereinare administered with a meal, the compositions and oral dosage forms canbe used in a variety of regimens for testosterone replacement therapyand other treatments or therapies. For example, in one embodiment, atestosterone replacement therapy for twice daily oral dosing is providedcomprising: (a) 2 (or 3) different dose strength oral dosage formshaving different amounts of testosterone undecanoate; (b) 3 dosingregimens providing for 3 different daily doses of testosteroneundecanoate; (c) both (a) and (b); or (d) a pharmaceutically equivalentversion thereof. In one aspect, the testosterone replacement therapyprovides steady state serum levels of testosterone (C_(avg)) to a malehaving testosterone deficiency or in need of said therapy in the rangeof about 300 ng/dL to about 1140 ng/dL. In one aspect, the testosteronereplacement therapy provides steady state serum levels of testosterone(C_(avg)) to a male having testosterone deficiency or in need of saidtherapy in the range of about 400 ng/dL or 435 ng/dL to about 1140ng/dL. In one aspect, the testosterone replacement therapy providessingle dose C_(max) levels of serum testosterone at steady state to apopulation of males (e.g., more than 30, 40, 50, 75, 100, 150 or 200males) having testosterone deficiency, or in need of said therapy, ofless than 2500 ng/dL in at least 95% of the population of males, lessthan 1500 ng/dL in at least 85% of the population of males; or a serumtestosterone C_(max) of about 1800 ng/dL to about 2500 ng/dL in 10% orless of the population of males having testosterone deficiency. In oneaspect, the testosterone replacement therapy has one of the dosage formshaving from about 140 to 160 mg testosterone undecanoate and the otherdosage form has from about 215 mg to about 250 mg testosteroneundecanoate. In one aspect, the testosterone replacement therapy caninclude a third dose strength that has from about 280 mg to about 320 mgof testosterone undecanoate. In one specific aspect, the third dosestrength has about 300 mg testosterone undecanoate. In one aspect, thetestosterone replacement therapy has one of the dosage forms having fromabout 145 to 155 mg testosterone undecanoate and the other dosage formhas from about 220 mg to about 230 mg testosterone undecanoate. In oneaspect, the testosterone replacement therapy has one the of dosage formshaving about 150 mg testosterone undecanoate and the other dosage formhas about 225 mg testosterone undecanoate. In one aspect, thetestosterone replacement therapy has one the of dosage forms having fromabout 60 to 90 mg testosterone undecanoate and the other dosage form hasfrom about 100 mg to about 130 mg testosterone undecanoate. In oneaspect, the testosterone replacement therapy has one of the dosage formshaving from about 70 to 80 mg testosterone undecanoate and the otherdosage form has from about 107 mg to about 118 mg testosteroneundecanoate. In one aspect, the testosterone replacement therapy has oneof dosage forms having about 75 mg testosterone undecanoate and theother dosage form has about 112.5 mg testosterone. In one aspect, thetestosterone replacement therapy has 3 dosing regimens providing for 3different daily doses of testosterone undecanoate provide for a firstdaily dose of about 275 mg to about 325 mg of testosterone undecanoate,a second daily dose of from about 425 mg to about 490 mg of testosteroneundecanoate and a third daily dose of about 575 mg to about 625 mg oftestosterone undecanoate. In one aspect, the testosterone replacementtherapy provides for 3 different daily doses of testosteroneundecanoate—providing for a first daily dose of about 300 mg oftestosterone undecanoate, a second daily dose of about 450 testosteroneundecanoate and a third daily dose of about 600 mg of testosteroneundecanoate. In one aspect, the testosterone replacement therapycomprises: 2 dosage forms, one having about 75 mg of testosteroneundecanoate and the other dosage form having about 112.5 testosteroneundecanoate; 3 dosing regimens, a first dosing regimen comprisingadministration of two dosage forms twice a day, each dosage form havingabout 75 mg testosterone undecanoate, a second dosing regimen comprisingadministration of two dosage forms twice a day each dosage form havingabout 112.5 mg testosterone undecanoate, and a third dosing regimencomprising administration of four dosage forms twice a day each dosageform having about 75 mg testosterone undecanoate or a pharmaceuticallyequivalent version thereof. In one aspect, the testosterone replacementtherapy comprises: 2 dosage forms, one having about 150 mg oftestosterone undecanoate and the other dosage form having about 225testosterone undecanoate; 3 dosing regimens, a first dosing regimencomprising administration of one dosage form twice a day each dosageform having about 225 mg testosterone undecanoate, a second dosingregimen comprising administration of two dosage forms twice a day eachdosage form having about 150 mg testosterone undecanoate, and a thirddosing regimen comprising administration of two dosage forms twice a dayeach dosage form having about 150 mg testosterone undecanoate or apharmaceutically equivalent version thereof. As described herein,administration refers to administration to a subject in need oftestosterone replacement e.g., a hypogonadal male or a male having lowtestosterone levels or a symptom thereof. According to this embodiment,the dosage form can be a capsule with the fill containing at particularamount (e.g., 112.5 mg) of TU at about 15 wt % loading, 63 wt % Maisine35-1, 16 wt % Cremophor RH 40, and 6 wt % PEG 8000 or a pharmaceuticallyequivalent formulation thereof, a bioequivalent formulation thereof, ora combination thereof. Thus, these results support a drug label thatindicates or a method that includes that the oral testosteronereplacement therapy (oral formulation) is taken (1) “WITH A MEAL” or (2)“WITH MEAL, BUT NOT ON EMPTY STOMACH” or (3) “WITH FAT CONTAINING FOOD”not specifying fat content. In an alternative aspect, the drug label mayindicate or the method includes that the formulation is taken “WITHMEAL, BUT NOT LOW FAT”. In an alternative aspect, the drug label mayindicate or the method includes that the formulation is taken “WITHMEAL, BUT NOT HIGH FAT”. In an alternative aspect, the drug label mayindicate or the method includes that the formulation is taken “WITHSTANDARD OR NORMAL MEAL”.

Accordingly, an oral dosage form can be provided in a container having alabel that indicates that the oral dosage is to be taken (1) “WITH AMEAL”, (2) “WITH MEAL, BUT NOT ON EMPTY STOMACH”, (3) “WITH FATCONTAINING FOOD” not specifying fat content, (4) “WITH MEAL, BUT NOT LOWFAT”, (5) “WITH MEAL, BUT NOT HIGH FAT”, or (6) “WITH STANDARD OR NORMALMEAL”. Other suitable labels can also be included on the label of thecontainer, such as those described herein. Any suitable container can beused. Non-limiting examples of suitable containers can include a bottle,a pouch, a blister package, and other similar packaging that is known inthe art.

As described herein an oral TRT (testosterone replacement therapy) isprovided. The TRT has three different daily doses which commence with aninitial dosing regimen having a specific daily dose of testosteroneundecanoate that lasts for a period of time e.g., at least 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks. After this period oftime on the initial dosing regimen, a dose titration measurement orassessment is made. The purpose of the dose titration assessment ormeasurement is to determine if the daily dose should remain the same asa daily dose of the initial regimen or whether the daily dose should beincreased or decreased. The dose titration measurement or assessment ismade by determining serum testosterone concentrations within a specificamount of time (e.g., window of time) after administration of a singledose of the initial regimen at steady state. Three options are possiblebased on the result of this measurement or assessment. A level of serumtestosterone that is too high will result in a decrease in the totaldaily dose of testosterone undecanoate, a level of serum testosteronethat is too low will result in an increase in the daily dose oftestosterone undecanoate and intermediate levels of serum testosteronewill result in no change of the daily dose of testosterone undecanoate.It was surprisingly found that the TRT described herein providesnumerous benefits to individuals or populations of individuals in needof such therapy and in particular it was found that certain formulationsare bioequivalent with respect to different food conditions. Thus, theoral dosage forms used in the TRT can be (1) “WITH A MEAL” or (2) “WITHMEAL, BUT NOT ON EMPTY STOMACH” or (3) “WITH FAT CONTAINING FOOD” notspecifying fat content. In an alternative aspect, the drug label mayindicate or the method includes that the formulation is taken “WITHMEAL, BUT NOT LOW FAT”. In an alternative aspect, the drug label mayindicate or the method includes that the formulation is taken “WITHMEAL, BUT NOT HIGH FAT”. In an alternative aspect, the drug label mayindicate or the method includes that the formulation is taken “WITHSTANDARD OR NORMAL MEAL”. The TRT described herein provides for threedifferent daily doses of testosterone undecanoate formulated for oraladministration that are typically divided into two administrations e.g.,a morning dose and an evening dose. The three daily doses oftestosterone undecanoate are in the 280-320 mg range, the 430 mg to 490mg range, and the 580 mg to 620 mg range. These daily doses are providedby two to eight unit dosage forms per day.

According to this TRT, a subject or patient e.g., hypogonadal malestarts on an initial dose or initial dosing regimen that provides aspecific amount of testosterone undecanoate per day for an initialperiod of time (e.g., greater than one, two, or three weeks) that is tobe administered with food. This initial daily dose is in the range ofabout 430 mg to 490 mg TU per day (or 435 mg to 465 mg TU per day, 440mg to 460 mg TU per day, 445 mg to 455 mg TU per day, or about 450 mgper day). After the initial period of time, a dose titration measurementor assessment is made. The dose titration measurement is made bydetermining serum testosterone levels at a specific time (e.g., within 1to 12 hours, 1 to 11 hours, 1 to 10 hours, 1 to 9 hours, 1 to 8 hours, 1to 7 hours, 1 to 6 hours, 1 to 5 hours, 1 to 4 hours, 2 to 10 hours, 2to 9 hours, 2 to 8 hours, 2 to 7 hours, 2 to 6 hours, 2 to 5 hours, 2 to4 hours, 1 to 3 hours, 2 to 3 hours, 3 to 4 hours, 4 to 5 hours, 3 to 5hours, 4 to 6 hours, 3 to 6 hours, 3 to 8 hours, or 4 to 6 hours; or atabout 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 hours±0.5, 1, 1.5, or 2hours) after a single dose of the initial regimen when the patient is atsteady state. Depending of the serum testosterone level obtained fromthe dose titration measurement, the patient can receive a maintenanceregimen that has the same daily dose as the initial regimen or the dailydose is increased or decreased. Typically, the patient or subject isthen maintained on the maintenance regimen, although one or moreadditional dose titration measurements or dose titrations can be made.The therapy described herein is typically administered as a twice a daytherapy with a meal, so a 300 mg TU dose is administered as 150 mg witha meal twice a day; a 450 mg dose is administered as 225 mg with a mealtwice a day; and a 450 mg dose is administered as 225 mg with a mealtwice a day.

The dose titration of the TRT described herein was found to besurprisingly robust and beneficial for patients receiving the therapy,especially in view of the food effect study described in the Examples.In a specific aspect, the up or down titration are at about 70 to 80 mgTU per dose (e.g., 75 mg TU) or about 140 to 160 mg (e.g., 150 mg TU)per day TU. Typically, the doses of TU are administered with a meal.Thus, the methods described herein can include an initial daily dosefollowed by a dose titration. The dose titration is used to determinethe maintenance daily dose which is within plus/minus 75%, 50%, 40% or35% of the initial daily dose.

In one embodiment, a therapy for treating a male having a baseline serumtestosterone level of 300 ng/dL or less is provided, said therapycomprising: (a) 2 oral dosage forms having different amounts oftestosterone undecanoate; (b) 3 dosing regimens providing differentdaily doses of testosterone undecanoate; (c) both (a) and (b); or (d) apharmaceutically equivalent version thereof. In one aspect, the higherand lower daily doses are within about 40% of the intermediate dose. Inone aspect, the therapy provides single dose C_(max) levels of serumtestosterone at steady state levels to a population of males havingtestosterone deficiency, or in need of said therapy, of (a) less than2500 ng/dL in at least 95% of the population of males; (b) less than1500 ng/dL in at least 85% of the population of males; a serumtestosterone C_(max) of about 1800 ng/dL to about 2500 ng/dL in 10% orless of the subjects in the group; or a combination thereof. In oneaspect, a patient receiving the therapy has a dose titration assessment.In one aspect, the dose titration assessment comprises determining avalue of serum testosterone at from about two to eight hours afterreceiving a dose of testosterone undecanoate. In one aspect, a patienthaving (a) a low serum testosterone level at two to eight hours afterreceiving a single dose of testosterone undecanoate at steady statereceives a higher dose of testosterone undecanoate; (b) a high serumtestosterone level at two to eight hours after receiving a single doseof testosterone undecanoate at steady state receives a lower dose oftestosterone undecanoate; (c) an intermediate serum testosterone levelafter receiving a single dose of testosterone undecanoate at steadystate an intermediate dose of testosterone undecanoate; or (d) acombination thereof. In one aspect, the dose titration assessmentcomprises determining the serum testosterone level during a windowperiod within two to eight hours after receiving a dose of testosteroneundecanoate. Low serum testosterone can be defined as less than 500,450, 400, 350, 300, 250 or 200 ng/dL. High serum testosterone can bedefined as greater than 500, 550, 600, 650, 700, 750, 800 or 850 ng/dL.Intermediate serum testosterone can be defined as a range of valuesdefined by low and high serum testosterone levels in the previous twosentences.

Typically, the unit dosage forms contain an amount of TU as describedherein and one or more pharmaceutically acceptable carriers e.g.,additives. In one aspect, the unit dosage form is a tablet or capsule.In one aspect, the unit dosage form has a pharmaceutically acceptablecarrier lipophilic additive, a hydrophilic additive, a solidifying agentor a combination thereof. In one aspect, the unit dosage form whentested using a USP type 2 apparatus in about 1000 mL 8% w/v Triton X100solution in water at 37.0±0.5 at 100 rpm releases at least 60 wt % TU at15 minutes and less than 100 wt % TU at 15 minutes. In one aspect, theunit dosage form has a pharmaceutically acceptable carrier lipophilicadditive, a hydrophilic additive, a solidifying agent, or a combinationthereof. In one aspect, the unit dosage form when tested using a USPtype 2 apparatus in about 1000 mL 8% w/v Triton X100 solution in waterat 37.0±0.5 at 100 rpm releases less than 90 wt % TU at 30 minutes andgreater than 90 wt % TU at 120 minutes. In one aspect, the unit dosageform when tested using a USP type 2 apparatus in about 1000 mL 8% w/vTriton X100 solution in water at 37.0±0.5 at 100 rpm releases greaterthan 90 wt % TU at 30 minutes. The unit dosage forms usually contain alipophilic additive although this is not absolutely required. The dosageforms can also contain a hydrophilic additive, a solidifying agent, orone or more other additives. The pharmaceutically acceptable carriers aselected such that the oral dosage form is pharmaceutically equivalent,bioequivalent, in respect to serum testosterone levels to a capsule withthe fill containing from 50 mg to 350 mg TU (e.g., 75 or 112.5 mg TU) atabout 15 wt % loading, 63 wt % Maisine 35-1, 16 wt % Cremophor RH 40,and 6 wt % PEG 8000). In respect to bioequivalent formulations, in oneaspect, bioequivalent refers to steady state. In another aspect,bioequivalent refers to single dose. In yet another aspect,bioequivalent refers to food effect bioequivalent. Food effectbioequivalent refers to bioequivalence of the formulation under low fatversus standard fat meals, standard fat versus high fat meals, low fatversus high fat meals or a combination thereof.

In one embodiment, specific examples of oral dosage forms that arebioequivalent, pharmaceutically equivalent or both, to a capsule withthe fill containing from 50 mg to 350 mg TU (e.g., 75 or 112.5 mg TU) atabout 15 wt % loading, 63 wt % Maisine 35-1, 16 wt % Cremophor RH 40,and 6 wt % PEG 8000) include tablets, capsules, sachets, lozenges,granules, powders, sprinkle, suspension, liquids or combinationsthereof. In another embodiment, the dosage form is coated. In oneembodiment, the solid composition can be a matrix. In one embodiment,the solid oral dosage form is a tablet or a capsule. In anotherembodiment oral dosage form is a multiparticulate oral dosage form. Inanother embodiment, the composition can be multiparticulate. Regardlessof the type, the oral dosage forms or compositions can be formulated toprovide immediate, modified, delayed, sustained, extended, and/orcontrolled release of the testosterone undecanoate. The immediate,modified, delayed, extended, pulsatile, and/or controlled release can beachieved by any method known in the art so long as it does not interferewith the function of the solid oral dosage forms. Non-limiting examplesof such methods includes coatings, polymers, and the like. In oneembodiment, the oral dosage form can be uncoated. In one embodiment thesolid composition of the invention is a solid dispersion, solidsolution, molecular dispersion, co-precipitate, amorphate, solidifiedsuspension, admixture, eutectic mixture, melt extrude, drug-carriercomplex, thermosetting system, or combinations thereof. Thus, the oraldosage form has a drug label indicating or the method includes that theoral testosterone replacement therapy (oral formulation) is taken (1)“WITH A MEAL” or (2) “WITH MEAL, BUT NOT ON EMPTY STOMACH” or (3) “WITHFAT CONTAINING FOOD” not specifying fat content. In an alternativeaspect, the drug label may indicate or the method includes that theformulation is taken “WITH MEAL, BUT NOT LOW FAT”. In an alternativeaspect, the drug label may indicate or the method includes that theformulation is taken “WITH MEAL, BUT NOT HIGH FAT”. In an alternativeaspect, the drug label may indicate or the method includes that theformulation is taken “WITH STANDARD OR NORMAL MEAL”.

In some embodiments, the oral dosage forms the present invention can bemanufactured as tablet or capsule dosage forms either by dry granulationmethods, or by wet granulation methods. For example, testosteroneundecanoate can be combined with one or more pharmaceutically acceptablecarrier and blended to get a homogenous mixture which can be compressedinto a tablet or disposed into a capsule. In another embodiment, thehomogenous mixture can be kneaded with a binder solution to get a wetgranulate mass which can be dried and sized, for example by passingthrough ASTM mesh #30. The resulting granules can be optionally blendedwith pharmaceutical aids such as diluents, lubricants, disintegrantsetc., and disposed into capsules or compressed into tablets. In anotherparticular case, the tablets can be coated. In one embodiment the tabletis a matrix tablet. In another embodiment, the tablet can bemulti-layered tablet dosage form which can achieve releasecharacteristics that can accommodate dose splitting.

The oral dosage forms can also be formulated using melt-extrusionprocesses alone or in combination with other known processes. Forexample, in one embodiment, an amount of testosterone undecanoate can behomogeneously combined with a sufficient amount of one or more carriersubstances prior to undergoing extrusion. The carrier suitable for thecompositions of this invention, specifically melt extrusion process, canbe lipophilic or hydrophilic carrier. Combinations of lipophilic andhydrophilic carriers may also be used.

The terms “melt” and “melting” should be interpreted broadly, andinclude not only the alteration from a solid state to a liquid state,but can also refer to a transition to a glassy state or a rubbery statein which it is possible for one component of the mixture to get embeddedmore or less homogeneously into the other. In particular cases, onecomponent can melt and the other component(s) can dissolve in the melt,thus forming a solution which, upon cooling, may form a solidcomposition having advantageous properties. In another particular case,one component can melt and the other component(s) can suspend thusforming a suspension which upon cooling may form a solid suspensionhaving advantageous properties.

The melt-extruded solid compositions used to make the oral dosage formsof the present disclosure can be granular, multiparticulates, pellets,beads, mini-tablets or tablets. The melt-extruded solids can be usedalone as the solid oral dosage form or can be disposed into capsules orformed into tablets.

The carrier for a melt-extruded composition and/or dosage form caninclude, but is not limited to, carriers such as ethyl cellulose,cellulose acetate phthalates, glyceryl distearate, acrylic acid andmethacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethylmethacrylates, cyanoethyl methacrylate, aminoalkyl methacrylatecopolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acidalkylamide copolymer, poly(methyl methacrylate), poly(methacrylic acid)(anhydride), methyl methacrylate, polymethacrylate, stearic acid,poly(methyl methacrylate) copolymer, polyacrylamide, aminoalkylmethacrylate copolymer, poly(methacrylic acid anhydride), and glycidylmethacrylate copolymers.

In one embodiment, the carrier for a melt-extruded oral dosage form canbe one or more pharmaceutically acceptable polymers including, but notlimited to polyvinyl alcohol, polyvinyl pyrrolidone, polyethyleneglycols having molecular weight of about 1000 to about 20,000, gelatin,carbomer, poloxamer, hydroxypropyl methyl cellulose; hydroxypropyl ethylcellulose hydroxypropyl cellulose, and carboxymethyl cellulose. It isnoteworthy that some pharmaceutical carriers can be used in more thanone manufacturing process, such as a wet milling or dry milling processas well as a melt extrusion process.

In certain embodiments, the at least one pharmaceutically acceptablecarrier of any pharmaceutical composition provided herein comprises atleast one hydrophilic carrier. In specific embodiments, the hydrophiliccarrier is a hydrophilic triglyceride. In more specific embodiments, thehydrophilic triglyceride is a polyoxylated castor oil, or a polyoxylatedhydrogenated castor oil. In some embodiments, any pharmaceuticalcomposition provided herein has a lipophilic carrier (e.g., additive) orcombination of lipophilic carriers. In certain embodiments, anypharmaceutical composition provided herein comprises a lipophiliccarrier and less than 10 wt % or less than 5 wt % of a hydrophiliccarrier.

In one embodiment, the lipophilic additive can include a lipophilicsurfactant.

As used herein a surfactant is considered to be a lipophilic surfactantwhen it has an HLB value of 10 or less. Various lipophilic surfactantscan be used including, but not limited to mono-, di-glycerides of fattyacids like glyceryl monolinoleate (e.g., Maisine® 35-1), mono- and diglycerides of caprylic, capric acid (e.g., Capmul® MCM), glycerylmonooleate, reaction mixtures of alcohols or polyalcohols with a varietyof natural and/or hydrogenated oils such as PEG-5 hydrogenated castoroil, PEG-7 hydrogenated castor oil, PEG-9 hydrogenated castor oil, PEG-6corn oil (e.g., Labrafil® M 2125 CS), PEG-6 almond oil (e.g., Labrafil®M1966 CS), PEG-6 apricot kernel oil (e.g., Labrafil®M 1944 CS), PEG-6olive oil (e.g., Labrafil®M 1980 CS), PEG-6 peanut oil (e.g., Labrafil®M1969 CS), PEG-6 hydrogenated palm kernel oil (e.g., Labrafil®. M 2130BS), PEG-6 palm kernel oil (e.g., Labrafil® M 2130 CS), PEG-6 triolein(e.g., Labrafil® M 2735 CS), PEG-8 corn oil (e.g., Labrafil® WL 2609BS), PEG-20 corn glycerides (e.g., Crovol® M40), PEG-20 almondglycerides (e.g., Crovol® A40), lipophilicpolyoxyethylene-polyoxypropylene block co-polymers (e.g., Pluronic® L92,L101, L121 etc.); propylene glycol fatty acid esters, such as propyleneglycol monolaurate (e.g., Lauroglycol FCC), propylene glycol ricinoleate(e.g., Propymuls), propylene glycol monooleate (e.g., Myverol P-06),propylene glycol dicaprylate/dicaprate (e.g., Captex® 200), andpropylene glycol dioctanoate (e.g., Captex® 800), propylene glycolmono-caprylate (e.g., Capryol® 90); propylene glycol oleate (e.g.,Lutrol OP2000); propylene glycol myristate; propylene glycol monostearate; propylene glycol hydroxy stearate; propylene glycolricinoleate; propylene glycol isostearate; propylene glycol mono-oleate;propylene glycol dicaprylate/dicaprate; propylene glycol dioctanoate;propylene glycol caprylate-caprate; propylene glycol dilaurate;propylene glycol distearate; propylene glycol dicaprylate; propyleneglycol dicaprate; mixtures of propylene glycol esters and glycerolesters such as mixtures composed of the oleic acid esters of propyleneglycol and glycerol (e.g., Arlacel® 186); sterol and sterol derivativessuch as cholesterol, sitosterol, phytosterol, phytosterol fatty acidesters, PEG-5 soya sterol, PEG-10 soya sterol, PEG-20 soya sterol, andthe like; glyceryl palmitostearate, glyceryl stearate, glyceryldistearate, glyceryl monostearate, or a combination thereof; sorbitanfatty acid esters such as sorbitan monolaurate (e.g., Arlacel 20),sorbitan monopalmitate (e.g., Span-40), sorbitan monooleate (e.g.,Span-80), sorbitan monostearate, and sorbitan tristearate, sorbitanmonolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitantrioleate, sorbitan sesquioleate, sorbitan tristearate, sorbitanmonoisostearate, sorbitan sesquistearate, and the like; fatty acids suchas capric acid, caprylic acid, oleic acid, linoleic acid, myristic acid,menthol, menthol derivatives, lecithin, phosphatidyl choline, bilesalts, and the like, and mixtures thereof. It is important to note thatsome lipophilic surfactants may also function as the solubilizercomponent of the compositions and oral dosage forms.

In one embodiment, the lipophilic surfactant can be selected from thegroup consisting of glyceryl monolinoleate (e.g., Maisine® 35-1), mono-and di glycerides of caprylic, capric acid (e.g., Capmul® MCM), glycerylmonooleate, propylene glycol mono caprylate, propylene glycol oleate,propylene glycol monostearate, propylene glycol monolaurate, propyleneglycol mono-oleate, propylene glycol dicaprylate/dicaprate, sorbitanmonooleate, PEG-5 hydrogenated castor oil, PEG-7 hydrogenated castoroil, PEG-9 hydrogenated castor oil, PEG-6 corn oil, PEG-6 almond oil,PEG-6 apricot kernel oil, PEG-6 olive oil, PEG-6 peanut oil, PEG-6hydrogenated palm kernel oil, sorbitan monolaurate (e.g., Arlacel 20),sorbitan monopalmitate, sorbitan monooleate, sorbitan monostearate,sorbitan tristearate, sorbitan monolaurate, sorbitan monopalmitate,sorbitan monooleate, sorbitan trioleate, sorbitan sesquioleate, sorbitantristearate, sorbitan monoisostearate, and combinations thereof. In someembodiments, the lipophilic surfactants can comprise at least about 10,20, 30, 40, 50, 60, 70, 80, or 90 wt % of the total pharmaceuticallyacceptable carrier. It should be noted that the combinations of two ormore lipophilic surfactants from the same or different classes thereinare also within the scope of this invention and are together can bereferred to as the lipophilic surfactant, unless otherwise stated.

In one embodiment, the composition/dosage form has a hydrophilicadditive or a hydrophilic additive which can be a hydrophilicsurfactant. A surfactant is considered to be a hydrophilic surfactantwhen it has an HLB value of greater than 10. Non-limiting examples ofhydrophilic surfactants include non-ionic surfactants, ionic surfactantsand zwitterionic surfactants. Specifically the hydrophilic surfactantssuitable for the current invention include, but not limited toalcohol-oil transesterification products; polyoxyethylene hydrogenatedvegetable oils; polyoxyethylene vegetable oils; alkyl sulphate salts,dioctyl sulfosuccinate salts; polyethylene glycol fatty acids esters;polyethylene glycol fatty acids mono- and di-ester mixtures;polysorbates, polyethylene glycol derivatives of tocopherol and the likeIt should be noted that the combinations of two or more hydrophilicsurfactants from the same or different classes are within the scope ofthis invention and are together can be referred to as the hydrophilicsurfactant unless explicitly specified. In one embodiment, thehydrophilic additive can be a hydrophilic surfactant. Non-limitingexamples of hydrophilic surfactants can include PEG-8 caprylic/capricglycerides, lauroyl macrogol-32 glyceride, stearoyl macrogol glyceride,PEG-40 hydrogenated castor oil, PEG-35 castor oil, sodium laurylsulfate, sodium dioctyl sulfosuccinate, polyethylene glycol fatty acidsmono- and di-ester mixtures, polysorbate 80, polysorbate 20,polyethylene glycol 1000 tocopherol succinate, phytosterols, phytosterolfatty acid esters, and mixtures thereof.

Suitable additives utilized in various embodiments described hereininclude, by way of non-limiting example, adsorbing agents,anti-adherents, anticoagulants, antifoaming agents, antioxidants,anti-caking agents, anti-static agents, binders, bile acids, bufferants,bulking agents, chelating agents, coagulants, colorants, co-solvent,opaquants, congealing agents, coolants, cryoprotectants, diluents,dehumidifying agents, desiccants, desensitizers, disintegrants,dispersing agents, enzyme inhibitors, glidants, fillers, hydratingagent, super disintegrants, gums, mucilages, hydrogen bonding agents,enzymes, flavorants, humectants, humidifying agents, lubricant oils,ion-exchange resins, lubricants, plasticizers, pH modifying agents,preservatives, solidifying agent, solvents, solubilizers, spreadingagent sweeteners, stabilizers, surface area enhancing agents, suspendingagent, thickeners, viscosity increasing agents, waxes and mixturesthereof.

Some non-limiting examples of the additives suitable for the presentdisclosure may be: alcohols and/or polyols (e.g., ethanol, isopropanol,butanol, benzyl alcohol, ethylene glycol, propylene glycol, glycerol,sorbitol, mannitol, dimethyl isosorbide, polyethylene glycol, fatty acidalcohol, vinyl alcohol polypropylene glycol, polyvinylalcohol,tocopherols, cellulose cyclodextrins, other derivatives, forms, mixturesthereof, or the like); ethers of polyethylene glycols having an averagemolecular weight of about 200 to about 20,000 (e.g., tetrahydrofurfurylalcohol PEG ether, methoxy PEG, or the like); amides (e.g.,2-pyrrolidone, 2-piperidone, 8-caprolactam, N-alkylpyrrolidone,N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam,dimethylacetamide, polyvinylpyrrolidone and the like.); esters (e.g.ethyl propionate, tributylcitrate, acetyl triethylcitrate, acetyltributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate, ethylbutyrate, triacetin, propylene glycol monoacetate, propylene glycoldiacetate, 8-caprolactone and isomers thereof, 6-valerolactone andisomers thereof, gamma-butyrolactone and isomers thereof; and otheradditives known in the art, such as dimethyl acetamide, dimethylisosorbide, N-methylpyrrolidones, monooctanoin, diethylene glycolmonoethyl ether, or the like); amino acids (e.g., p-aminobenzamidine,sodium glycocholate) mesylate; amino acids and modified amino acids(e.g., aminoboronic acid derivatives and n-acetylcysteine; peptides andmodified peptides (e.g., bacitracin, phosphinic acid dipeptidederivatives, pepstatin, antipain, leupeptin, chymostatin, elastin,bestatin, phoshporamindon, puromycin, cytochalasin potatocarboxypeptidase inhibitor, amastatin, or the like); polypeptide proteaseinhibitors; mucoadhesive polymers (e.g., polyacrylate derivatives,chitosan, cellulosics, chitosan-EDTA, chitosan-EDTA-antipain,polyacrylic acid, carboxymethyl cellulose etc.) or the like; orcombinations thereof.

Some more examples of suitable additives for compositions and/or dosageforms described herein include, by way of non-limiting example, talc,magnesium stearate, silica (e.g., fumed silica, micronized silica,magnesium aluminum silicate etc.) and/or derivatives, polyethyleneglycols, surfactants, waxes, oils, cetyl alcohol, polyvinyl alcohol,stearic acid, stearic acid salts, stearic acid derivatives, starch,hydrogenated vegetable oils, hydrogenated castor oils, sodium benzoate,sodium acetate, leucine, PEG, alkyl sulfate salts; acetylatedmonoglycerides; long-chain alcohols; silicone derivatives; butylatedhydroxy toluene (BHT), butylated hydroxyl anisole (BHA), gallic acid,propyl gallate, ascorbic acid, ascorbyl palmitate,4-hydroxymethyl-2,6-di-tert-butyl phenol, dry starch, dry sugars,polyvinyl pyrrolidones, starch paste, methacrylic copolymers, bentonite,sucrose, polymeric cellulose derivatives, shellac, sugar syrup; cornsyrup; polysaccharides, acacia, tragacanth, guar gum, xanthan gums;alginates; gelatin; gelatin hydrolysate; agar; sucrose; dextrose; PEG,vinyl pyrrolidone copolymers, poloxamers; pregelatinized starch,sorbitol, glucose); acetic acid, hydrochloric acid, hydrobromic acid,hydriodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid,acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonicacid, amino acids, ascorbic acid, benzoic acid, boric acid, butyricacid, carbonic acid, citric acid, fatty acids, formic acid, fumaricacid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lacticacid, maleic acid, methanesulfonic acid, oxalic acid,para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid,salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid,thioglycolic acid, toluenesulfonic acid and uric acid, vinegar,pharmaceutically acceptable bases, such as an amino acid, an amino acidester, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodiumhydrogen carbonate, aluminum hydroxide, calcium carbonate, magnesiumhydroxide, magnesium aluminum silicate, synthetic aluminum silicate,synthetic hydrotalcite, magnesium aluminum hydroxide,diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine,triethylamine, triisopropanolamin; salt of a pharmaceutically acceptablecation and an anion; EDTA and EDTA salts; titanium dioxide, food dyes,lakes, natural vegetable colorants, iron oxides, silicates, sulfates,magnesium hydroxide and aluminum hydroxide; halogenated hydrocarbons,trichloroethane, trichloroethylene, dichloromethane,fluorotrichloromethane, diethylether, trehalose, phosphates, citricacid, tartaric acid, gelatin, dextran and mannitol, lactose, mannitol,sodium chloride, potassium chloride, spray-dried lactose, hydrolyzedstarches, directly compressible starch, microcrystalline cellulose,cellulosic derivatives, sorbitol, sucrose, sucrose-based materials,calcium sulfate, dibasic calcium phosphate, dextrose, croscarmellosesodium, starch, starch derivatives, clays, gums, cellulose, cellulosederivatives, alginates, crosslinked polyvinylpyrrolidone, sodium starchglycolate and microcrystalline cellulose, magnesium oxide, magnesiumcarbonates; desensitizers, spray-dried flavors, essential oils, ethylvanillin, styrene/divinyl benzene copolymers, quaternary ammoniumcompounds, polyethylene glycol, citrate esters (such as triethylcitrate, acetyl triethyl citrate, acetyltributyl citrate), acetylatedmonoglycerides, glycerin, triacetin, propylene glycol, phthalate esters(e.g., diethyl phthalate, dibutyl phthalate), castor oil, sorbitol anddibutyl sebacate, ascorbic acid, boric acid, sorbic acid, benzoic acid,and salts thereof, parabens, phenols, benzyl alcohol, and quaternaryammonium compounds; alcohols, ketones, esters, chlorinated hydrocarbonswater; sweeteners (e.g., maltose, sucrose, glucose, sorbitol, glycerinand dextrins, aspartame, saccharine, saccharine salts, glycyrrhizin),viscosity modifiers, sugars, polyvinylpyrrolidone, cellulosics,polymers, gums and/or alginates.

In one embodiment, additives may also be materials such as proteins(e.g., collagen, gelatin, Zein, gluten, mussel protein, lipoprotein);carbohydrates (e.g., alginates, carrageenan, cellulose derivatives,pectin, starch, chitosan); gums (e.g., xanthan gum, gum Arabic);spermaceti; natural or synthetic waxes; carnuaba wax; fatty acids (e.g.,stearic acid, hydroxystearic acid); fatty alcohols; sugars; shellacs,such as those based on sugars (e.g., lactose, sucrose, dextrose) orstarches; polysaccharide-based shellacs (e.g., maltodextrin andmaltodextrin derivatives, dextrates, cyclodextrin and cyclodextrinderivatives); cellulosic-based polymers (e.g., ethyl cellulose, methylcellulose, microcrystalline cellulose, sodium carboxymethyl cellulose,hydroxypropylmethyl cellulose, ethyl cellulose, hydroxypropyl cellulose,HPMC acid succinates, cellulose acetate, cellulose nitrate, celluloseacetate butyrate, cellulose acetate trimellitate, carboxymethylethylcellulose, hydroxypropylmethyl cellulose phthalate), shellacs;inorganics, such as dicalcium phosphate, hydroxyapatite, tricalciumphosphate, talc and titania; polyols, such as mannitol, xylitol andsorbitol; polyethylene glycol esters; and polymers, such as alginates,poly(lactide coglycolide), gelatin, crosslinked gelatin, and agar-agar.Non-limiting examples of compounds (e.g., additives) that can be used asat least a part of the pharmaceutically acceptable carrier includewithout limitation celluloses; dextrins, gums, carbomers, methacrylates,sugars, lactoses, inorganic carbonates, oxides, chlorides, sulphates andthe like; salts of calcium; salts of magnesium; salts of fatty acids;inorganic and organic acids, bases and salts; propylene glycol;glycerols; fatty acids; fatty alcohols; fatty acid esters; glycerolesters; mono-, di- or triglycerides; edible oils; omega oils; vegetableoils, hydrogenated vegetable oils; partially or fully hydrogenatedvegetable oils; glycerol esters of fatty acids; waxes; alcohols;gelatin; polyethylene glycol; polyethylene oxide co-polymers; silicates;antioxidants, tocopherols, sugar stearates, starches, shellac, resins,proteins, acrylates; methyl copolymers; polyvinyl alcohol; starch;phthalates; and combinations thereof.

In one embodiment, the additive may include at least one componentselected from celluloses, dextrins, gums, carbomers, methacrylates,inorganic carbonates, salts of calcium, salts of magnesium, fatty acids,fatty acid esters, gelatin, lactoses, polyethylene glycol, polyethyleneoxide co-polymers, silicates, partially hydrogenated vegetable oils,fully hydrogenated vegetable oils, waxes, antioxidants, tocopherol,sugar stearates, starches, shellac, resins, proteins, and combinationsthereof.

In another embodiment, the additive may include at least one componentselected from celluloses, dextrins, gums, carbomers, methacrylates,sugars, lactoses, inorganic carbonates, salts of calcium, salts ofmagnesium, salts of fatty acids, inorganic and organic acids, bases andsalts, propylene glycol, glycerols, fatty acids, fatty alcohols, fattyacid esters, glycerol esters, mono-glycerol esters of fatty acids,di-glycerol esters of fatty acids, mixtures of mono-glycerol anddi-gylcerol esters of fatty acids, omega oils, waxes, alcohols, gelatin,polyethylene glycol, polyethylene oxide co-polymers, silicates,antioxidants, tocopherol, sugar stearates, starches, shellac, resins,proteins, acrylates, methyl copolymers, polyvinyl alcohol, starch,phthalates, and combinations thereof.

Non-limiting examples of additives as release modulators that may beused include lipophilic resins; ethyl cellulose (EC), methylethylcellulose (MEC), carboxymethyl ethylcellulose (CMEC), hydroxyethylcellulose (HEC), cellulose acetate (CA), cellulose propionate (CPr),cellulose butyrate (CB), cellulose acetate butyrate (CAB), celluloseacetate phthalate (CAP), cellulose acetate trimellitate (CAT),hydroxypropyl methyl cellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methyl celluloseacetate trimellitate (HPMCAT), ion-exchange resin; poloxamers; andethylhydroxy ethylcellulose (EHEC) tocopherol; shellac; and combinationsthereof. Non-limiting examples of lipidic lipophilic release modulatorsinclude fatty acids; mono-, di-, tri-esters of fatty acids withglycerol; sucrose esters with fatty acids; cetyl alcohol; stearic acid;glyceryl monostearate; glyceryl distearate; glyceryl tristearate;glyceryl palmitostearate; hydrogenated castor oil; butyl and glycolesters of fatty acids; oleic acid; cetyl alcohol; stearyl alcohol;cetostearyl alcohol; hydrogenated vegetable oil; waxes; bees wax; lard;omega fatty acid esters; hydrogenated soybean oil; hydrogenatedvegetable oil; hydrogenated cottonseed and castor oil; partiallyhydrogenated soybean oil; partially hydrogenated castor oil; partiallysoy and cottonseed oil; phospholipids; hydrogenated oils, and theirderivatives and combinations thereof.

In some embodiments, the pharmaceutical composition (e.g., oral dosageform) provided herein is formulated, e.g., with a viscosity enhancingagent or solidifying agent, to provide a solid, a semi-solid, a gel, ajelly, a paste, or the like. In some embodiments, the oral dosage formis a liquid. Non-limiting examples of formulations (and for use in themethods described herein) are given in the tables below.

TABLE A Capsule A1 Capsule A2 Component % w/w % w/w TestosteroneUndecanoate (50-350 mg) 1-50 10-30 Hydrophilic Carrier 0-90  0-30Lipophilic Carrier 1-90 40-70 Other Additive(s) 0-20  0-10

TABLE B Capsule B1 Capsule B2 Component % w/w % w/w TestosteroneUndecanoate 1-50 10-30 (75, 112.5, 150, 225, or 300 mg) HydrophilicCarrier 0-90  0-30 Lipophilic Carrier 1-90 40-70 Other Additive(s) 0-20 0-10

TABLE C Capsule C1 Capsule C2 Component % w/w % w/w TestosteroneUndecanoate 5-40 10-30 (75, 112.5, 150, 225, or 300 mg) HydrophilicCarrier 0-90  0-30 Lipophilic Carrier 1-90 40-70 Solidifying Agent 1-20 3-10

TABLE D Capsule D1 Capsule D2 Component % w/w % w/w TestosteroneUndecanoate (75, 112.5, 150, 225, 5-40 10-30 or 300 mg) Cremophor RH 400-90  0-30 Glyceryl Monolinoleate 1-90 40-70 PEG 8000 1-20  3-10

TABLE E Capsule E1 Capsule E2 Component % w/w % w/w TestosteroneUndecanoate (75, 112.5, 150, 225, 10-25 13-23 or 300 mg) Cremophor RH 40 0-25 10-20 Glyceryl Monolinoleate 30-90 40-70 Solidifying agent  0-20 3-10

Bioequivalent, pharmaceutically equivalent formulations having the druglabel as described herein or for use in the method included herein caninclude those described about in Tables A-E or e.g., in reference to aformulation having 50 mg to 350 mg testosterone undecanoate (e.g., inone aspect either 75 mg or 112.5 mg TU) at about 15 wt % loading, about63 wt % Maisine 35-1, about 16 wt % Cremophor RH 40, and about 6 wt %PEG 8000 as follows.

(1) Varying the loading (or amount) of testosterone undecanoate.(2) Varying the amount of Maisine 35-1, exchanging Maisine 35-1 foranother lipophilic additive (in varying amounts) or including one ormore additional lipophilic additives in addition to Maisine 35-1 (invarying amounts). In one aspect, the other lipophilic additive is afatty acid or ester thereof such as a fatty acid glyceride (e.g., mono-,di- or tri-glyceride) or a reaction mixture of a fatty acid glyceridewith an alcohol e.g., polyethylene glycol, or a combination thereof.(3) Varying the amount of Cremophor RH 40, exchanging Cremophor RH 40for another hydrophilic additive (in varying amounts) or including oneor more additional hydrophilic additives in addition to Cremophor RH 40(in varying amounts). In one aspect, the other hydrophilic additive is apolyoxylated hydrogenated vegetable oil. In another aspect, the otherhydrophilic additive is an ionic or non-ionic surfactant.(4) Varying the amount of PEG 8000 (or not include PEG 8000), exchangingPEG 8000 for another solidifying agent (in varying amounts) or includingone or more additional solidifying agents in addition to PEG 8000 (invarying amounts). In one aspect, the other solidifying agent is a highmolecular weight PEG (2000 mw or more), a phytosterol or ester thereof,solid (at room temperature) fatty acids or mono- or di-glycerides) andthe such.(5) Including one or more additional pharmaceutically acceptablecarriers (in varying amounts); or(6) A combination of one or more of (1)-(5).

EXAMPLES

The following examples are provided to promote a more clearunderstanding of certain embodiments of the present invention, and arein no way meant as a limitation thereon.

Example 1: Food Effect Clinical Study

This study was a single-center, open-label, randomized, cross-over,single-dose, four period, four-treatment study to examine the effect offood (fasted vs. high fat) and fat content of food on pharmacokineticsof testosterone & metabolites. 14 subjects were enrolled and 13completed the study. 225 mg of TU (2 capsules (capsule fill containing112.5 mg TU at about 15 wt % loading, 63 wt % Maisine 35-1, 16 wt %Cremophor RH 40, and 6 wt % PEG 8000) administered with:

-   -   Treatment A: Standard-Fat with 20-35 wt % fat;    -   Treatment B: Low-Fat with ˜15 wt % fat;    -   Treatment C: High-Fat with ˜50 wt % fat; and    -   Treatment D: overnight fasting, to hypogonadal males.

The meals were as follows in Table I with quantity specified as grams(g) or [% total calories].

TABLE I Total Energy Treatment (kcal) Carbohydrates Proteins Lipids A:Standard 842.5 115.2 g 27.7 g 30.1 g Fat [54.7 wt %] [13.2 wt %] [32.1wt %] B: Low Fat 911.7   173 g 17.8 g 16.5 g [75.9 wt %] [7.8 wt %][16.3 wt %] C: High Fat 930.7   82 g 30.3 g 53.5 g [35.2 wt %] [13.0 wt%] [51.7 wt %]The results from the clinical trial are summarized in Table II below,which demonstrates bioequivalence for Cmax and Cavg for a standard mealversus a low fat meal or high fat meal and low fat versus high fatmeals.

TABLE II C_(max) C_(avg) Test Condition (ng/dL) (ng/dL) Point estimate[90% CI bounds] Interpolation of Phase 3 food fat content Standard vs.Low  98 [82-117] 99 [91-107] Standard Vs. high 103 [86-123] 114[105-124] Effect of food fat content spread (low to high) Low Vs. High105 [88-125] 115 [106-125]

Thus, it was surprisingly discovered that oral testosterone undecanoatecompositions can be administered to hypogonadal males with a mealwithout fat content of the meal substantially effecting bioavailability.This result is unexpected and in direct contrast to the results obtainedwith other testosterone undecanoate oral formulations reported in theliterature whose bioavailability is dependent on meal fat content.

Given this information one of ordinary skillin the present arts would becapable of providing oral testosterone undecanoate formulation that arebioequivalent to the formulation used in this study, that arebioequivalent for C_(max), AUC_((0-t)), AUC_((0-∞)), C_(avg), or acombination thereof at low, standard, and high fat conditions as well asstandard versus low fat, standard versus high fat and low versus highfat.

The results of this study are also summarized in Tables III & IV below.

TABLE III Comparative Pharmacokinetic Analysis for Testosterone Exposurefollowing Administration of Formulation A under Fed Conditions withMeals of Varying Fat Content (Study, N = 13) Low Fat High Fat (~16.5 g)Standard Fat (~30.1 g) (~53.5 g) Parameter Meal² Meal¹(Reference) Meal³Cmax (ng/dL) Mean (% CV) 1570 (35%) 1560 (31%) 1680 (44%) [Range][844-2610] [746-2700] [692-2910] Point Estimate 98.26 100 102.72 (90% CI(82.18-117.48) (85.92-122.82) bounds) AUC 0-24 h (ng*h/dL) Mean (% CV)10429 (19%) 10421 (16%) 11974 (18%) [Range] [7529-14083] [7817-14394][8729-15184] Point Estimate 98.86 100 114.06 (90% CI (90.99-107.42)(104.98-123.93) bounds) Abbreviations: AUC = area under the curve; CI =confidence interval; Cmax = maximum observed serum concentration; CV =coefficient of variation ¹30% total calories derived from fat content inthe meal consistent with Phase 3 recommended meal ²15% total caloriesderived from fat content in the meal ³50% total calories derived fromfat content in the meal

TABLE IV Pharmacokinetic Parameters for Serum Total Testosteronefollowing Formulation A Administration under Fasted vs Fed Conditions inHypogonadal Men Fasted (N = Fed¹ (N = Parameter 14) 13) Cmax (ng/dL)Mean (% CV) 562 (26%) 1680 (44%) [Range] [342-880] [692-2910] AUC 0-24 h(ng*h/dL) Mean (% CV) 7423 (19%) 11974 (18%) [Range] [5597-10787][8729-15184] Abbreviations: AUC = area under the curve; Cmax = maximumobserved serum concentration; CV = coefficient of variation ¹50% totalcalories derived from fat content in the meal

TABLE 5 Pharmacokinetics of Dihydrotestosterone PK Standard ParameterFat Low Fat High Fat Fasted C_(max) 166 152 185 63 (GLSM, ng/dL) Pointestimate Reference 92 [81-105] 111 [98-127] 38 [34-44] [90% CI bounds]AUC _(0-t) 1580 1439 1893 807 (GLSM, ng*h/dL) Point estimate Reference91 [82-102] 120 [107-134] 51 [46-57] [90% CI bounds] C_(avg) 66 60 79 34(GLSM, ng/dL) Point estimate Reference 91 [82-102] 120 [107-134] 51[46-57] [90% CI bounds]Thus, these results support a drug label indicating that the oraltestosterone replacement therapy is taken (1) “WITH A MEAL” or (2) “WITHMEAL, BUT NOT ON EMPTY STOMACH” or (3) “WITH FAT CONTAINING FOOD” notspecifying fat content. In the alternative, the drug label may indicate“TAKE IT WITH MEAL, BUT NOT LOW FAT”. In another alternative, the druglabel may indicate “TAKE IT WITH MEAL, BUT NOT HIGH FAT”. It yet anotheralternative, the drug label may indicate “TAKE IT WITH STANDARD ORNORMAL MEAL”.

Example 2: Bioequivalent Formulations and Oral Dosage Forms

The ordinary skilled artisan in view of these results can design andtest formulations for bioequivalence (e.g., food effect bioequivalence)using the present disclosure.

Formulations for testing in a food effect study as described in Example1 (or another appropriate designed study) can be designed e.g., by:

(1) varying the loading of testosterone undecanoate;(2) varying the amount of Maisine 35-1, exchanging Maisine 35-1 foranother lipophilic additive (in varying amounts) or including one ormore additional lipophilic additives in addition to Maisine 35-1 (invarying amounts);(3) varying the amount of Cremophor RH 40, exchanging Cremophor RH 40for another hydrophilic additive (in varying amounts) or including oneor more additional hydrophilic additives in addition to Cremophor RH 40(in varying amounts);(4) varying the amount of PEG 8000 (or not include PEG 8000), exchangingPEG 8000 for another solidifying agent (in varying amounts) or includingone or more additional solidifying agents in addition to PEG 8000 (invarying amounts);(5) including one or more additional pharmaceutically acceptablecarriers (in varying amounts); or(6) a combination of one or more of (1)-(5).

Typically, these formulations will be suited for soft gelatin or hardgelatin capsules. Other dosage forms are also contemplated for use inthe present disclosure including tablets, sachets, lozenges, granules,powders, sprinkle, suspension, liquids or combinations thereof.

Example 3: Clinical Trial to Show Bioequivalence

To determine if a Test formulation is bioequivalent to the formulationused in Example 1, a bioequivalence study is performed under the same orsimilar conditions. One of ordinary skill in the art can design andperform a bioequivalence study in view of the results presented inExample 1. Test formulations can be generated according to thisdisclosure or more particularly Example 2. The bioequivalence study isone that may support the filing of an Abbreviated New Drug Applicationat the US FDA or similar application in jurisdictions outside of theUnited States with the appropriate regulatory agency.

It is understood that the above-described various types of compositions,dosage forms and/or modes of applications are only illustrative ofpreferred embodiments of the present invention. Numerous modificationsand alternative arrangements may be devised by those skilled in the artwithout departing from the spirit and scope of the present invention andthe appended claims are intended to cover such modifications andarrangements. Thus, while the present invention has been described abovewith particularity and detail in connection with what is presentlydeemed to be the most practical and preferred embodiments of theinvention, it will be apparent to those of ordinary skill in the artthat variations including, but not limited to, variations in size,materials, shape, form, function and manner of operation, assembly anduse may be made without departing from the principles and concepts setforth herein.

1. A method for replacement therapy in a male for a condition associatedwith a deficiency or absence of endogenous testosterone, said methodcomprising: orally administering to a male having a condition associatedwith a deficiency or absence of endogenous testosterone, with a meal, apharmaceutical composition comprising from about 50 mg to about 300 mgof testosterone undecanoate and a pharmaceutically acceptable carriersaid pharmaceutical acceptable carrier being selected to providebioequivalent amounts of serum testosterone, testosterone undecanoate,dihydrotestosterone, or dihydrotestosterone undecanoate levels to saidmale when administered with (1) meals containing standard fat ascompared to low fat and high fat, (2) meals containing low fat ascompared to high fat, or both (1) and (2).
 2. The method of claim 1,wherein said pharmaceutical composition has about 75 mg, about 112.5 mg,about 150 mg, about 225 mg, or 300 mg of testosterone undecanoate. 3.The method of claim 1, wherein said pharmaceutically acceptable carrierselected to provide bioequivalent amounts of serum testosterone levelsto said male for meals containing low, standard fat and high fat.
 4. Themethod of claim 1, wherein said method provides a serum testosteroneCavg in the range of 300 ng/dL to 1100 ng/dL.
 5. The method of claim 1,wherein said administering occurs twice-a-day.
 6. The method of claim 1,wherein said method comprises administering from 285 mg to about 625 mgof testosterone undecanoate per day.
 7. The method of claim 1, whereinsaid composition comprises a lipophilic additive.
 8. The method of claim1, wherein said composition comprises a hydrophilic additive.
 9. Themethod of claim 1, wherein said pharmaceutical composition (1) ispharmaceutically equivalent to an oral pharmaceutical composition havingabout 75 mg or about 112.5 mg of testosterone undecanoate at about 15 wt% loading, about 63 wt % Maisine 35-1, about 16 wt % Cremophor RH 40,and about 6 wt % PEG 8000 or (2) has about 75 mg or about 112.5 mg oftestosterone undecanoate at about 15 wt % loading, about 63 wt % Maisine35-1, about 16 wt % Cremophor RH 40, and about 6 wt % PEG
 8000. 10. Themethod of claim 1, wherein said method comprises administering thepharmaceutical composition as 2, 3, 4, 5, 6, 7, or 8 unit dosage formsper day.
 11. A method for replacement therapy in a male for conditionsassociated with a deficiency or absence of endogenous testosterone, saidmethod comprising: orally administering to a male having a conditionassociated with a deficiency or absence of endogenous testosterone, witha meal having about 10 wt % to 50 wt % fat, a pharmaceutical compositioncomprising from about 50 mg to about 300 mg of testosterone undecanoateand a pharmaceutically acceptable carrier said pharmaceutical acceptablecarrier being selected to provide bioequivalent amounts of serumtestosterone, testosterone undecanoate, dihydrotestosterone, ordihydrotestosterone undecanoate levels to said male when administeredwith meals containing (1) standard fat as compared to low fat and highfat, (2) low fat to high fat, or (3) a combination thereof.
 12. Themethod of claim 11, wherein said pharmaceutical composition (1) ispharmaceutically equivalent to an oral pharmaceutical composition havingabout 75 mg or about 112.5 mg of testosterone undecanoate at about 15 wt% loading, about 63 wt % Maisine 35-1, about 16 wt % Cremophor RH 40,and about 6 wt % PEG 8000 or (2) has about 75 mg or about 112.5 mg oftestosterone undecanoate at about 15 wt % loading, about 63 wt % Maisine35-1, about 16 wt % Cremophor RH 40, and about 6 wt % PEG
 8000. 13. Themethod of claim 11, wherein said method provides a serum testosteroneCavg in the range of 300 ng/dL to 1100 ng/dL.
 14. The method of claim11, wherein said method comprises administering from 285 mg to about 625mg of testosterone undecanoate per day.
 15. The method of claim 11, saidadministering occurs twice-a-day.
 16. A pharmaceutical composition fororal administration comprising testosterone undecanoate and apharmaceutical acceptable carrier said pharmaceutical compositionproviding bioequivalent amounts of serum testosterone undecanoate,testosterone, dihydrotestosterone, dihydrotestosterone undecanoate or acombination thereof to a male for a condition associated with adeficiency or absence of endogenous testosterone when administered witha meal (1) containing medium fat as compared to high fat or low fat or(2) containing low, standard and high fat.
 17. The pharmaceuticalcomposition of claim 16, wherein said pharmaceutical composition ispharmaceutically equivalent to an oral pharmaceutical composition havingabout 75 mg or about 112.5 mg of testosterone undecanoate at 15 wt %loading, 63 wt % Maisine 35-1, 16 wt % Cremophor RH 40, and 6 wt % PEG8000.
 18. The pharmaceutical composition of claim 16, further comprisinga monoglyceride, a diglyceride or a combination thereof in amount ofgreater than about 10 wt % and has less than about 50 wt % triglyceride.19. A pharmaceutical composition for oral administration that ishypogonadal male serum testosterone bioequivalent to a formulationcomprising 15 wt % testosterone undecanoate, about 63 wt % Maisine 35-1,about 16 wt % Cremophor RH 40, and about 6 wt % polyethylene glycol 8000under medium fat as compared to low fat and high fat with the provisothat the formulation does not comprise about 15 wt % testosteroneundecanoate, about 63 wt % Maisine 35-1, about 16 wt % Cremophor RH 40,and about 6 wt % polyethylene glycol
 8000. 20. The pharmaceuticalcomposition of claim 19, wherein said pharmaceutical composition ispharmaceutically equivalent to an oral pharmaceutical composition havingabout 75 mg or about 112.5 mg of testosterone undecanoate at 15 wt %loading, 63 wt % Maisine 35-1, 16 wt % Cremophor RH 40, and 6 wt % PEG8000. 21-42. (canceled)